Process for conidendrol making



'Patented sept. so, 1952 l Paoonss Foa coNIDENDRoL MAKING William M. Hearon, Camas, Wash., assigner to Crown" Zcllerbach Corporation, Camas, Wash.,

. I a corporation of Nevada Application December 5, 1949, Serial No. 131,253

fs claims. (o1. 26o- 344er No Drawing;

"This inventionv relates toconidendrol andfto droxymethyl) -2-naphthoic acid-gamma-lactone,

is a derivative of conidendrin, a Wood extractive substance' present in the sulfite-Waste liquor obtained during the pulping of western hemlock andother trees and isolated from the liquor by treatment with suitableorganic liquids. It is a isms.l Because ofthe several reactive functional groupsl present;` it is a valuable starting material for thesynthesis of .pharmaceuticals andother organic compounds. A The structuresv of conidendrin and of conidenother unwanted by-products.

drol are indicated bythe general formula given below,` the formula -being that 'of' conidendrin whenjR. is a methyll groupiCHa),V andthat of l on.

coriidernirin and conidendrol occur "as" diasterioisomers,` a fact whichl may be attributable to an inversion taking place at the carbon atomi-'t adjacent thel carbonyl group of the lacto-ne ring,

cojrideridmrnomiberger. 54, 2389 1921. 1 have fundby lthe present' investigation that conidendrol also.;l exists in' the form of twogeometricl isomers, the one being termed lalpha. conidendrol since. lit y `has the` same basic conilguration as the normal conidendrin, andthe otherv being termed *beta conidewndrol because fof itsl correspondence ingeoinetric structure to beta oonidendrin.

` As is 'apparent from a` consideration ofthe general formulagiven above, conidendrol differsvv structurally from conidendrin in that 'the methoxyl groups present in the latter have been coni-1"* verted to phenolic groups. The demethylation'Y reaction required to effect this conversion is diff iicult to consummate, however, because .ofjth'e' great sensitivity of conidendrin to various chemie` cal reagents. Being a aphenol, it is very easily halogenated, as by means of the free .bromine which may be present in hydrobromic acid when the latter is usedas a demethylating agent.H Beingareducing agent, it is sensitive to an oxidiz'- ing environment. Furthermore, since it containsv phenolicvgroups and a lactone ring, both o'fj arevery-reactive chemically, side reactions url, during the demethylation tov produce tars an The problem.v is. further complicated by the fact that reasonably strenuous conditions of reaction are required 'to effect the demethylation, this favoring' the occur-X rence of the side reactions. As a result,'attempts to demethylate conidendrin to form conidendrol using the great majority.v i of demethylating agents under various conditions result in the formation of a reaction product" comprising tarry substances, degradation Iprod-li',` ucts of conidendrin, and other icy-products from which complex mixture conidendrol cannot-be" separated as a'chemical individual, 'if itis infact presenttherein at all. (Fisher et al., J. Am. Oil Chemists Soc. 24: 340-343 (October 1947))l In acomprehensive .investigation'of processesllfor the demethylation of coniden'drin, I have vfoundv that, among the conventional demethylating agents which are not vsuccessful in the.conversion y of conidendrin to conidendrol, are variousofth l, mineral acids inciudinghydrochiorie acid, suifurie acid,.and nitric acid. Basic 'materals'such as sodium hydroxide also are unsuitable. stuivfurther inapplicable-are the, organic acidsv` such A as paratoiuene sulfonieiacid and thane Sinfonieacid. Attempts to use various'saits such aluminum chloride. aluminum ,lorc'imida-fanali,v boron trifluoride also 'have been unsuccessful.' I have discovered furthermore that,Mk of th Y various available demethylating agents, hydriodic' acidis unique in that through its use conidendrin mayr ber converted successfully vto pure falpha.M comdendrol in yieldsv of the -order of7% or better. 'raus for the first time; have been' able f to prepare. alpha conidendrol as a wh-itacrystal y line product having a. sharp melting pointand.- distinct ,chemical identity... Aisdwhenjiahav employed beta conidendrin as the subject :matter 'l means of` a' mutual solvent'.

of the demethylation, I have been able to prepare for the first time beta conidendrol of characn teristic melting point and other physical prop= erties. I also have found that hydriodic acid is an effective catalyst in rendering other demethylating yagents applicable in the conversion of conidendrinto pure conidendrol in high yields.

This action is obtained even though the hydricdic aelasoa vention, the hydrogen iodide, which normallyis suppliedr in the form of an aqueous solution, is

admixed with the conidendrin and with a mutualy solvent for the two materials. The resulting solution then is heated, with or without the applicationof r sup*eratmosplfieric pressure, and maintainedvat an elevated temperatureuntil the reaction l,is.complete. During this time, there are formed as'products* of the reaction methyl iodide,

reaction mixture, and c onidendrol which remains in solution in thesolvent medium. Afterr'completionV of the reaction, the excess hydrogen l iodideand solvent may be removed by distillationl and the residue taken up in hot wateryand f filtered to remove solidrimpurities, Upon cooling.

theQresulting aqueousv solution, the conidendrol is .deposited asl awhite, crystalline solid. l

t The amount of demethylating agent employed. infcarfiying out the process of the vinvention` yshouldbeat least about thetheoretical duantity required for. the'demethylation of. the coniden-k drin, i. 'e.' atlea'st' two /mols .for each mol of conidendrin. The upper limit of demethylating agent usagel is Vdeterminedprimarily by practical considerati'ons,'but normallyv would not exceedabout two andA one-half times'the theoretical amount.

VIt isjpreferred to employ slightly more than the theoretical quantity, e. g.r aboutv one and one- 'half timesI the theoretical. amount, this being which` is volatile and largely escapesV from the sui'cientf to' carry the reaction tov completionL with minimumformation` of undesirable by-y products.;

Where' a'mixture of hydriodicV acid yand another.,

demethylating agentv such as hydrobromic acid.

isusedgthe Itotal'am'ount of the dernethylating mixture used 'likewise is preferably slightly.. in

. excessief the theoretical quantity`,'the amount?, off'thel more expensive hydriodic'acid being less than about cnet-quarter of the theoretical.amount..A

This'ramountofhydriodic acid has' a pronounced catalyticeffect on the reaction, since, even thoughfl it is present in farvlessythan' the theoretical amount,v itY causes the reaction to take place.

smoothly ,andV to produce a pure product.

The conidendrinjand 'demethylating ,agent are maintained'in-solution during the reaction by preferred 'solvent for this purpose', although other suitable-solvents maybe 'employed such as pro'- Acetie acid is av picnic acid,-butyric acid, dioxan, and the like,

used'either-singly or'in admixture with each other: AsuilCientamOunt ofthe solvent should beemployed-to dissolve the conidendrin and dernethylating agent rapidly, and to keep*v them,

aswell as the products of the reaction. in solution.

duringthereactionv-period, From about'20% to about-l75%' byweight of acetic acid, based on the fweigvht" of n the 4reaction mixture, preferably 4 is employed. Below about 20% the time for solution of the conidendrin is markedly increased, and little, if any, benei'lt is obtained by increasing the amount ofv solvent above about 75%.

A secondary reducing agent preferably is also incorporated in the reaction mixture in amount sufficient to prevent theformation:` ofgfree halogen, e. g.v free iodine or freebromine'.' l This prevents halogenation of the conidendrin as a side reaction. f It also prevents the formation of hypo acids lfrom the combination of the iodine or the bromineA with the water content of the reaction mixture, thereby preventing the oxidation of the* conidendrin and the conidendrol as another undesirableiside reaction. A relatively minor proportiononly of reducing agent is necessaryV *to accomplish this purpose, for example from about 1 to about 3 parts by weight of re- .ducing agent for each 100 parts by Weight of demethylating agent. Examples of suitable reducing agents which may thusbe employed are red phosphorus, hypophosphorms` acid andthe; like.

from about 20% to L,about'7 5% of acetic,A acid as a solvent, temperatures Within `the rang'eorf.. bee tween about C. 'and about 125, C. arelsuitable,

atA atmospheric pressure. Inl'this case, the.; boiling, temperature of tlfiefmixture,l i. e. aftemperature of about 118"1C.l visa preferred,reactiontemav perature. Where the reaction is carriedout atkk elevated pressurese. g. pressures oiflfrom vabout., 5 p. s.'i. toabout, 100. p. s. i., somewhat ligheif,l temperatures may beused,lel g'. temperatures. of!k the order of l4'0b-150'C. v I Y l The time o'f heatingis variablel With. thev temperature, the concentratioiof. thev demethylating agent employed, and the pressure applied? .When using concentrated `hydriodic acid/at the morer elevated temperaturedand pressures, the react- 1v tion period may be onlya few minutes. Where' vtilling the reaction mixture, preferably under diminished pressure to remove excess acid and solvent, after which the residual material is disf solved in hot water, filtered hot, if necessary, and permitted to cool. As the aqueous solution cools, theA Vconidendrol llneform.l

Alternatively," the reaction' mixtueqmay' be diluted with about an equal volumeofwater and its acid content neutralized with sodium bicar* bonate or other base. Therv neutralized mixture'v then may be extracted with ether'for'reniovaljMy of the conidendrol and theether layer separated"`-` from the aque'ouslayer, afterjwhich the ether' 1 is removed Aby distillationfrom'the `sclidfconilin dendrol. The latter,thenlistakeup in hot water and crystallized therefrom inthemanner` indicated above;

sun another metrica-qerecovering tueacdni-#j dendrcl is to pour the; reaction m.ixturefdir'efctly'f'VVA The temperature at which thedemethylation.- is carried out Should besuiiicientto initiate. the.,A reaction without being so'high as to promote the` formation of decompositionproducts of the vtonie dendrinor conidendrol. Ingeneral, when using',

:is precipitated inl crystal?r Y" into'hotv water and permit .the resulting solution tol-cool. Thereupon the conidendrol will crystallize. directlyfromthe aqueous medium. n i

The product as obtained by crystallization from water contains two molecules of water of hydration and is a White crystalline solid melting at from 102 lC. to 103C. It may beconverted to the anhydrous condition by heating, e. g. by-heating at 95"` C. for onehour. The anhydrous product melts at 165 C. to 166 C. 0f the two forms, the dihydrate is the stable form under usual atmospheric conditions, the anhydrous material reverting to thevdihydrate upon exposure tothe atmosphere. y

Beta conidendrol is prepared in a `manner similar to that outlined above, except that beta conidendrin is used as a starting material rather than conidendrin in theform normally isolated from sulte waste liquor. Thus beta conidendrin as formed by the action of alcoholic sodium ethoxide on conidendrin (Holmburg, supra) may be dissolved inacetic acid or other suitable solvent and mixed with at least the theoretical amount of hydriodic acid, or a mixture of hydriodicvacid and another demethylating agent such as hydrobromic acid. The resulting mixture may be f EXAMPLE I Thisvexample illustrates the use of hydriodic acid at normal atmospheric pressure in-converting 4the conidendrin to alpha conidendrol.

Al mixture Vof 5 g. ilnely divided vconidendrin, 25 mi. 57% hydriodic acid, 25 ml. glacial acetic acid, and 0.5 red phosphorus was gently reiluxed minutes under an air condenser through which thev methyl iodide was allowed to 'escape as it was formed. vThe temperature of the mixture rose to .118 C. in 10 minutes and remained there during' the vrest of the refluxing period. The 4mix-v ture-wastransferred-t a distilling ilask'and 60 g. distillate removed by heating on a steam bath under reduced pressure from an aspirator. The syrupy-residue was taken up in 100 ml. hot water, filtered hot to remove the phosphorus, and alflowed to'cool.` i The nearly colorless precipitate was removed from the lter, washed with water and dried in air at room temperature giving 4.3 g.

or 76% of theory of alpha conidendrol dihydrate melting at 102-103" C. Heating the product at 100 C. for one hour produced the anhydrous material M; P. 165-166 C. which, however, re'A gained: two molecules of water by standingin air. ,y

` Z I a:|D-S3.5 (acetone, C=2, for dlhydrate) Anal; Calcd. for CiaHieOe: C, 65.9; H, 4.91; OCI-I3,

0.0. Found: C, 66.0; H, 4.91; OCH3, 0.09.

Calcd. for C1sH1eOe2H2O2 C, 59.3; H, 5.53. Found: C, 59.1; H', 5.32. f V

The ,conidendrol was soluble in hot vwater and f incold aqueous alkalivor carbonate. It reduced Fehlings solution -in 'the hot. and save an im mediate black. precipitate ofnsilverwith .'Iollens'fl reagent. An aqueous solution gave a dark green color with ferric chloride which turned to adeep red on the addition of sodium carbonate. It diS'-. i solved quickly in aqueous sodium lhydroxide to..

give a yellow solution turning almost. at once to green, then blue.

turning a deep red on heating.

In addition, the conidendrol was in methanol, ethanol, acetone, and acetic acid. It was soluble in diethyl ether, and slightly soluble in benzene and chloroform. It was'very slightly soluble in ligroin, yand insolubleinV cari-.f f

bon tetrachloride.

The identity of the alpha conidendroljwasvfrur'.- ther established by the preparation of two deriva-f r. tives..i. e. alpha conidendrol tetrabenzoate'-andil alpha tetramethyl conidendrol.

Alpha conidendrol tetrabeneoate.-A mixture'-` of 5 g. alpha conidendrol, 25 ml. benzoyl chloride! and 40 ml. dry pyridine was left at room temv:' The mixture .was takenr up in` diethyl ether and washed successivelywithdilute hydrochloric acid, water, ,dilute sodium.: carbonate, and water. The ether was dried over perature yfor 16 hours.

sodium sulfate and evaporated to a syrup Awhich was stirred on a steam bath with 200 ml. ethanol. whereupon a voluminous white, crystalline precipitate formed. Weight 7.7 g. or 68% of theory.

M. P. 17d-177 C. Recrystallizationiirom 2:1

ethanol-'acetone gave 7.0 g. (62%) melting at i'zs-iaoc.

ajb-76 (acetone, C122) Anai.Ca1ca..-ror 0481132010: C, 74.2; H.- 4.33.1=1

FoundLlC, 74.4; H, 4.41. i

Alpha tetramethyz conidendrol.- To afmixt'ure of 1.0 g. alpha conidendrol dihydrate, 3.0 ml. water, and3 ml. dimethyl sulfate, rapidly stirred, f was added f 5% aqueous. sodium hydroxide. over 1. s a 1.5.hour period. .the mixture being maintained slightly alkaline.` `After standing-0.5 hour, thc-tdark solution was made acid with diIutesulfuIic acid, to deposit a tar. Thev mixturethenwas heated on a steam bath forfour hours during. which time the tar became crystalline.v` yThe cooled mixture was ltered, Agiving l,.0g.4(95%=.4 yield) vor tan ,coloredpcrystals ,Three recrystallify i1; zations from hot ethanol gave white crystals melting at 1.-"17--1'78u C. Alpha dimethyl coni-.ref dendrin made V by-direct methylation ofv conidenf l drin .[Brauns,J.,0rg. Chemistry 10, 216 (1945)] meltedy at 179-180 C. and did not depress zthe melting point; of the methylated lalpha conidendrol.

EXAMPLE II This example illustrates vthe. use 0f -hydllodc acid under pressure in the conversion olif-conidendrn to alpha conidendrol. A mixture of 20 g. conidendrin, 19, ml. 57% hydriodic acid andr ml. glacial acetic acid washeated, with o'ccan.

sional shaking, for 'one hour at 140 C in aglass lined bomb. The syrup, afterremoval oi excess acids, was taken up in 500 ml. hot water which,

on cooling, deposited 14.2 g. (70% 'oftneorwj white'alpha conidendrol dihydrate, melting" at'`v This 1533101"1151?;Yiillustrates. the y of at 'E i Warming changed this to. f black, then brown, and finally to red. A soluftion in aqueous sodium carbonate was yellow,-'.-

very soluble orhydrobnomic'ana'.hydmodic acids inthe proc:-v f

essfofftheinvention. f,

Ac-inix'tureof 20 g1 conidencl'rin, .3Q-nil. 48%-y phorousfacid Waswreuxed for 3 hours. syrupir'emaininglafter the lexcess acidstwere ree moved was taken up` in' one litermofh'ot water,

lter'd and allowed-taccol givingl g.V (73% ot theory) of alpha coriinde'ndrol dihydrate melty ingatw100-101" C.

,l EXAMPLE 1v This-example illustrates" th-e preparation' ofbeta-f oonindendrol` by the Idemethylation ofl beta conindendrin.

Azmixture of gifbetaconidendrin, 25 ml. 57% hydri'odic acid .andV 25 mlrglacial acetic acid was reiiuxed` `for minutes.

sure,'.and the resulting-Syrup was dissolved in 125%ml`.-hot .Water Iwhich deposited 2,'8 g; (61% yield)of a mixtureof White and Ilorown crystals after standing four hours' at 50 C. andA 16 hours at'room temperature'. Recrystalliz'ation frorn40 The excess acids were.'V i removed on the steambath under reduced'zpres'- ml: hot -W-ater .containing 0.5 g; sodium.. s'ulteV gave-1.9Yg".`.(4l.% yield) oflwhite crystals-melting'.

Analcalca. forv ciernes-6:. c, 659; H, 491;,

OCHa, 0.0. Found: C, 661); H, 5.01; OCHa, 0.08.

The beta conindendrol was soluble" in hot"l Water, cold aqueous alkali, or sodium carbonate and in most of the common organic solvents.

It reduced hot Fehlings solution and gave an immediate black precipitate of silver withTol-Hl lens reagent. An aqueous solution of beta conidendrol gave a light green color with ferrie chloride Which-turned to deep Vred with-sodium carbonate. .'Beta coni-dendrol'dissolved quickly in" aqueoussodium hydroxidetto give a yellowsolutionv which .on heating turned .successively green, blue,r=black, brown, andred. A solution. of the substance in aqueous: sodium carbonate was yel-y low`,.turning.to orange onheating.

Beta conidendrol. tetr'aacetate.-This deri'vaA tiveoiibetacoriidendrn` was prepared by treating a susbensionroi4f'g.1beta conidendrol ini-20 -ml.`- acetic anhydr-ide'withonedrop'of concentrated soltionresulted which was'. left-at room terne perature `l-vhours.A Addition otwatergave 5.1- g.-

` (84%fyieid)' fc'o'lorl-ess. crystals melting at" F75-BFI C. Recystallization Afrom hot ethanolgave 4-.9

` agets't' the presently described process.

chloride' was reiiuxedl for`41/g houis 'The"a1'u' mlnum chloride complex was destroyed Witl hydrochl-oric acid and-*the s'olutionfextracted with kethyl ether. The ether solution was vWashed and driedv and the-'ether -evancurated;v leaving; aflighttan .iluiy vproduct-f vThisy was parti-ally"demeth-v could not be'- crystallized.;

Aluminum bromide.-A mixture of `r5 g.V coni-f `dendrin;v 200 ml. toluene and 8.7-g. of aluminum bromide was reiiuxed 4% hours. thesoluti-cn with,hydrochloricy acid and ether extraction gave several fractions, mainly of unreacted alphaV conidendrin. There was also present 2.5 gnof browngummy material:-

Treatment of consisting i of indefinite composition. Evidently it Was-a.`

mixture of vvdecompositionproducts.'- It could fnot be crystallized.vr y Y Hydrochloo'z'cacid. f-Conidendrin-in:Water and acetic acid solutions `wit/'as mixed with variousI` concentrations of hydrochloricgacid. Tempera'- turesY from to 200 C. and fvariousreactionf times- Wereinvestigated inl a s'eries of experiments Two results Were obtained. Either' the alpha oonidendrin was vunchanged. or it had .be-v

T-h'ere was `no intermediate come a black tar. product obtainable,

Patassivuml` hydroxide-effi@ Y grams l of coni-V dendrinwere mixed Withl 5 -g.I-potassium hydroxy ideandY-the mixture Was fused for 20 minutes.44

with ether. The residue from evaporation ofthe ether wasfa'mbrown powdercontaining.: 111.5%

methoxyl. It could not be crystallizedf Y f Sodium hydroxide-A solutionfof` 5 g. con'ident drin in ml. of 7% sodium hydroxide was held at 300C.for l 1/zhoi-irs. Al large'amount ofwhite material-.insoluble `infacol-,-loase or V organic sol-` Vents was,depositedvonthefglass liner. The solution -Was .extractedfwith ether, .gi-ying a black viscousntar vwhich could not becrystallizecl..

Nitric acidy-Concentratedor dilute` nitric acids reacted withconidendrin `in-thecold to releaselarge-aniounts of nitrogen oxides. These apparently` acted as oxidizingv agents;v preventingfthe formation :of a -stable-i-onidendrol or destroying l stima@ acidr-c'onidendiltreated witifeon-Q centrated sulfuric acid' turned black andeharredalmost immediately. Re'iluxing coniclendrin;withy sulfuric acid did notchange the,con-idendrin.-

solution' was vpoured into water.

action, hence was notconidendrol. The remaining portion of the solution was heated at 183 C.

for 25 minutes. The only product was a black Boron fluoride-A mixture? 'of '1` g. coriiden'"v drin in 10 ml. boron fluoride-methyl ethercoin-A .The T' e l plex n was 'warmed `j 'gently' fr"30,- minutes. solution' vasca-u ""us'lyedcjrs .inte water.

Hydrobromz'c acid.-A mixture of 2,0 g. purified conidendrin, 125 ml. acetic acid land 16 m1. V48% hydrobromic acid (1.25 Xtheory was placed in a bomb and heated at 142 C. for one hour withv constant agitation. The bomb was cooled. `opened, and the contents poured into 600 ml. of b'oiling water containing a little sodium bisulte. The dark brown solution `was not lightened by the addition of more sodium bsulte. The solution then was cooled and seeded with alpha conidendrol. After three days there was no precipitate of any kind. The solution was black and opaque. This result isin direct contrast to the result of the procedure outlined in Example II wherein a successful result was obtained using hydriodic acid. rather than hydrobromic acid, under substantially the same reaction conditions.

Having now 4described my invention in preferred embodiments, I claim:

1. The process for the production of conidendrolwhich comprises reacting conidendrin with a demethylating agent comprising hydriodic acid, the hydriodic acid being used in amount 'at least equal to labout two mols of hydriodic acid for each mol of conidendrin.

2. The process for the production of conidendrol which comprises reacting conidendrin with a. demethylating mixture comprising hydriodic yacid and a second demethylating agent, the de-y methylating mixture being used in amount at least equal to about two mols of demethylating mixture for each mol of conidendrin.

3. The process of claim 2 wherein the second demethylating agent comprises hydrobromic acid.

4. The process for the production of beta conidendrol which comprises reacting beta coniden- -drin with demethyiaung agent ecmprising hydriodic acid, the hydriodic acid being used in amount at least equal to about two mols of hydriodic acid for each mol of conidendrin.

5. The process for the production of beta conidendrol which comprises reacting betaconidendrin-with al demethylating mixture comprising hydriodic acid and a second demethylating agent, the demethylating mixture being used in amount at least equal to about two mols of demethylating agent for each mol of conidendrin, and the hy- -driodic acid constituent thereof being used in a minor but catalytic amount.

6. The process of claim 5 wherein the second demethylating agent comprises hydrobromic acid.

7. The process for the production of conidendrol which comprises reacting conidendrin at a temperature of between about C. and about C. with hydriodic acid in amount at least equal to about two mols of hydriodic acid for each mol of conidendrin.

8. The process for the production of conidendrol which comprises forming a solution of conidendrin and hydriodic acid in a mutual solvent therefor, and heating the resulting solution at a temperature of between about 95 C. and about 150 C., whereby to eiect the demethylation of the conidendrin and its conversion to conidendrol.

WILLIAM M. HEARON.

REFERENCES VCITED The following references are of record in the file. of this patent:

Scand.A (1949 vol. 3, pp. 982-984. 

1. THE PROCESS FOR THE PRODUCTION OF CONIDENDROL WHICH COMPRISES REACTING CONIDENDRIN WITH A DEMETHYLATING AGENT COMPRISING HYDRIODIC ACID, THE HYDRIODIC ACID BEING USED IN AMOUNT AT LEAST EQUAL TO ABOUT TWO MOLS OF HYDRIODIC ACID FOR EACH MOL OF CONIDENDRIN. 